Process for preparing the combination products of triamterene and hydrochlorothiazide

Abstract

A combination pharmaceutical composition is described, together with the process for manufacturing said pharmaceutical composition wherein the active ingredients, namely triamterene and hydrochlorothiazide, are incorporated into a solid dosage form via a single wet granulation process utilizing an acid component. Said process simplifies the formulation and manufacturing, permits greater uniformity, and increases in vitro dissolution.

What is claimed is: 
     
       1. A process for producing a pharmaceutically active composition having combined diuretic, antihypokalemic and antihypertensive activity comprising the steps of (a) blending finely divided particles of a triamterene-active pteridine ingredient, a finely-divided hydrochlorothiazide-active benzothiadiazide and pharmaceutically acceptable inert ingredients to form a homogeneous mixture;   (b) adding to said homogeneous mixture a granulation liquid which is prepared by dispersing/dissolving a suitable binder and an acid component in a solvent to form a wet mass;   (c) milling of said mass to form granules; and   (d) blending the resulting granules with additional pharmaceutically acceptable inert ingredients wherein the weight ratio of said triamterene active ingredient to said hydrochlorothiazide active ingredient in the resulting composition is sufficient to control the hypokalemic effect induced by hydrochlorothiazide.   
     
     
       2. A process for producing a phgarmaceutically active composition having combined diuretic, antihypokalemic and antihypertensive activity comprising the steps of (a) blending finely divided particles of triamterene, finely divided particles of hydrochlorothiazide and a wicking, binding, disintegration agent to form a homogeneous mixture;   (b) adding to said homogeneous mixture a granulation liquid which is prepared by dispersing/dissolving a suitable binder and malic acid in the presence of water to form a wet mass;   (c) milling of said wet mass to form granules;   (d) drying of the wet granules;   (e) sizing of the dried granules; and blending of said sized granules with a lubricant agent and a disintegrant agent so that in the resulting composition the weight ratio of said triamterene to said hydrochlorothiazide is sufficient to control the hypokalemic effect induced by hydrochlorothiazide.   
     
     
       3. The process according to claim 2 wherein the amount of malic acid is about 5 to 45 percent on a triamterene weight basis. 
     
     
       4. The process according to claim 2 wherein the amount of water is about 50 to 650 percent on a triamterene weight basis. 
     
     
       5. A process according to claim 2 wherein the traimterene:hydrochlorothiazide weight ratio is from 1.25 to 2.00:1. 
     
     
       6. A process according to claim 5 wherein the traimterene: hydrochlorothiazide weight ratio is about 1.5:1. 
     
     
       7. A method of treating hypertension comprising administering a solid antihypertensive diuretic medication wherein said solid medication is composed essentially of hydrochlorothiazide and triamterene and wherein said solid medication is formed by blending finely divided particles of triamterene, finely divided particles of hydrochlorothiazide and a wicking, binding, disintegration agent to form a homogeneous mixture,   adding to said homogeneous mixture a granulation liquid which is prepared by dispersing/dissolving a suitable binder and malic acid in the presence of water to form a wet mass,   milling of said wet mass to form granules,   drying of the wet granules,   sizing of the dried granules, and blending of said sized granules with a lubricant agent and a disintegrant agent so that in the resulting composition the weight ratio of said triamterene to said hydrochlorothiazide is sufficient to control the hypokalemic effect induced by hydrochlorothiazide.   
     
     
       8. A method according to claim 7 wherein said solid medication is formulated as a tablet by compression. 
     
     
       9. A method according to claim 7 wherein said solid medication is formulated as a capsule. 
     
     
       10. A method according to claim 7 wherein the triamterene:hydrochlorothiazide weight ratio is from 1.25 to 2.00:1. 
     
     
       11. A method according to claim 10 wherein the triamterene: hydrochlorothiazide weight ratio is about 1.5:1. 
     
     
       12. A pharmaceutical combination composition having combined diuretic, antihypokalemic and antihypertensive activity wherein said composition is prepared by blending finely divided particles of triamterene, finely divided particles of hydrochlorothiazide and a wicking, binding, disintegration agent to form a homogeneous mixture,   adding to said homogeneous mixture a granulation liquid which is prepared by dispersing/dissolving a suitable binder and malic acid in the presence of water to form a wet mass,   milling of said wet mass to form granules,   drying of the wet granules,   sizing of the dried granules, and blending of said sized granules with a lubricant agent and a disintegrant agent so that in the resulting composition the weight ratio of said triamterene to said hycrochlorothiazide is sufficient to control the hypokalemic effect induced by hydrochlorothiazide.   
     
     
       13. A composition according to claim 12 wherein the triamterene:hydrochlorothiazide weight ratio is from 1.25 to 2.00:1. 
     
     
       14. A composition according to claim 13 wherein the triamterene:hydrochlorothiazide weight ratio is about 1.5:1.